Colorectal cancer is the second most common cause of cancer-related death in the United States. In 2007, an estimated 153,760 new cases will be diagnosed and 52,180 deaths will occur (1). Epidermal growth factor receptor (EGFR), also known as HER-1 or erbB-1, is a transmembrane protein, a member of a human epithelial receptor tyrosine kinase family, and is widely expressed in colonic tissues (2). Activation of EGFR initiates signal transduction cascades that affect gene expression, cellular proliferation, inhibition of apoptosis, and angiogenesis (3). EGFR has shown prognostic value and is associated with poor survival, more aggressive behavior, and an increased risk of invasion/metastasis in colorectal cancers (4). Additionally, blocking EGFR ligand binding through interaction with therapeutic monoclonal antibody such as cetuximab and panitumumab has been shown to be an effective treatment for advanced colon cancer (5).
Two functional polymorphic variants of EGFR are known in the art. The first polymorphism is a single nucleotide change (G to A) leading to an arginine (Arg) to lysine (Lys) substitution in codon 497 (HER-1 R497K) in the extracellular domain within subdomain IV of the EGFR gene. An in vitro study has shown that the variant HER-1 497K has attenuated functions in ligand binding, growth stimulation, tyrosine kinase activation, and induction of proto-oncogenes (myc, fos, and jun) compared with the more prevalent “wild-type” HER-1 497R variant (6).
Another functional polymorphism is located within intron 1 of the EGFR gene. This polymorphism is associated with altering levels of EGFR transcription both in vitro and in vitro (7, 8). The length of this (CA)n dinucleotide polymorphism inversely correlates with transcriptional activity of the gene. In vitro models have shown more transcriptional activity in cell lines expressing the shorter polymorphic variant (16 CA repeats (SEQ ID NO: 1)) compared with the longer polymorphic variant (>20 CA repeats (SEQ ID NO: 2) (8)). In vitro human breast tumors seem to select the shorter number of CA repeats ensuring higher expression levels of EGFR, which in turn propagates tumor growth and development (7).
Considerable evidence is accumulating that supports gender-related differences in the development of colonic carcinomas, with women of all ages less likely to develop colon cancer (9-11). Large comprehensive studies such as the Women's Health Initiative have conclusively shown that postmenopausal women treated with estrogen replacement therapy have a significant reduction in both risk and rate of developing colon cancer (12, 13). The molecular mechanisms behind this protective effect against colon cancer are not fully understood. However, the colon does express both estrogen receptor β (14) and androgen receptor (15). Important functional linkage and bidirectional signaling between epidermal growth factor receptor (EGFR) and estrogen receptor have been shown (16). Important signaling regulation between EGFR and androgen receptor has also been shown (17). Because EGFR is affected by both female estrogen receptors (16) and male androgen receptors (17), EGFR may be a potential mediator of gender-related differences in colon cancer.
Although considerable research correlating polymorphisms has been reported, much work remains to be done. This invention supplements the existing body of knowledge and provides related advantages as well.